Technical Field
The present invention relates to novel highly stable topically applicable cosmetic and/or dermatological compositions comprising depigmenting agents for treating the skin of the face and/or body for the purposes of lightening the skin, evening skin tone and/or treating areas of hyperpigmentation.
Background of Related Art
Consumers of skin lightening products spend more than $1 billion annually in search of skin with an even tone on their faces, hands and bodies. The development of areas of hyperpigmentation on the skin is obviously of great concern to these individuals. The hyperpigmented areas are caused by a concentration of melanin in the keratinocytes located at or near the skin surface. Melanin pigment is produced in melanocytes in highly specialized organelles known as melanosomes. Melanocytes are found in several locations throughout the body, including in the bottom layer of the skin's epidermis, the iris of the eye and the hair. Manufacturing of melanin begins when melanin-making enzymes are activated and transform the amino acid tyrosine to intermediates of the end product, melanin. The actual production of melanin begins in the melanosomes. Inside human melanosomes, a series of chemical reactions, catalyzed by enzymes, converts tyrosine into two types of melanin, eumelanin, which is brown or black in color, and pheomelanin, which is red or yellow.
Humans possess a variety of skin colors distributed among of races around the world. Epidermal coloration in humans is controlled by melanocytes, located in the base portion of the epidermis, where a complicated combination of cellular procedures is conducted (Raper, H. S., “The Anaerobic Oxidases,” Physiol. Rev. 1928, 8, 245-282; Mason, H. S., “The Chemistry of Melanin. III. Mechanism of the Oxidation of Trihydroxyphenylalanine by Tyrosinase, J. Biol. Chem. 1948, 172, 83-99; Cooksey, et al., “Evidence of the Indirect Formation of the Catecholic Intermediate Substrate Responsible for the Autoactivation Kinetics of Tyrosinase,” J. Biol. Chem. 1997, 272, 26226-26235; Chang T. S., “An Updated Tyrosinase Inhibitors,” Int. J. Mol. Sci. 2009, 10, 2440-2475). These processes, in addition to the catalytic reaction of tyrosinase, the major critical and rate-controlling step, result in the synthesis and transfer of a pigment, melanin. Melanin, which besides being responsible for skin color and tone, is the key physiological defense factor against sun injury, such as sunburn, photoaging and photocarcinogenesis. Therefore, tyrosinase is a recognized molecular target of discovery and development of hypopigmenting agents for medical dermal pigment conditions (disorders) and cosmetics (Chang T. S., “An Updated Tyrosinase Inhibitors,” Int. J. Mol. Sci. 2009, 10, 2440-2475).
Hyperpigmentation, hypopigmentation, and other pigmentation disorders are quite common and can be caused by a verity of factors, including genetics, living and daily working environment, some medical conditions, medications, excessive sun exposure, etc. Common pigmentation disorders include melasma (dark patches appearing during or after pregnancy) and liver spots (which often develop with age), and may arise as a side effect of birth control pills, and/or as a persistent result of acne, burns, bites and other skin injuries. Similarly, freckles, chloasma and pigmentary deposits after sun exposure tend to occur or increase or become difficult to lighten with increasing age, thus being one of the more disconcerting and/or common problems of skin care for persons of middle to advanced age. Post inflammatory hyper-pigmentation might occur following any inflammatory state of the skin such as chemical burns or following laser therapy. In order to obtain brighter/lighter skin or address pigmentation disorders effectively and simply, many compositions have been formulated. The use of such compositions is not limited to treating medical pigmentation disorders, but also in some cultures/markets merely for the purpose of changing or whitening ones natural healthy skin for cosmetic purpose.
A large number of agents and methods for skin depigmentation or hypopigmentation have been discovered, developed and used on cosmetic market. The most commonly and effectively employed hypopigmentation agent is hydroquinone (HQ). However, while effective, HQ has serious adverse side effect (D. C. Topping, et al., Food and Chemical Toxicology, 45 (2007) 70-78; J. C. English, et al., Fundam. Appl. Toxicol. 23 (1994) 391-396; J. C. English, et al., Fundam. Appl. Toxicol. 23 (1994) 397-406; R. Charlin, et al., International Journal of Dermatology, 2008, 47, 19-23; Y. M. Olumide, et al., International Journal of Dermatology, 2008, 47, 344-353; T. W. Tse, Journal of Dermatological Treatment 2010, 21, 272-275; R. J. Bqatman, et al., Journal of Toxicology and Environmental Health, 1996, 47:2, 159-172; R. Barale, et al., Mutation Research, 244 (1990) 15-20; M. L. Robertson, et al., Mutation Research, 249 (1991) 201-209; Q. Li, et al., Toxicol. Appl. Pharmacol. 1996, 139, 317-323; G. C. Jagetia, et al., Toxicology Letters, 93 (1997) 205-213; V. V. Subrahmanyam, et al., Toxicology, 62 (1990) 107-116), even though the cancer causal association was not clearly determined (D. E. Rollison, et al., Journal of Toxicology and Environmental Health, Part B, 2006, 9:413-439). In many parts of the world, including the European Union and China, hydroquinone is banned for cosmetic product. The Chinese FDA regulation for hydroquinone use is that the highest allowed concentration for hydroquinone in any cosmetic products is 0.002% (20 ppm). Although to date sales of cosmetic products containing hydroquinone are allowed in the United States, safety concerns have also been expressed by the US FDA. There remains a need for stable formulations for a safer alternative to hydroquinone.
The activity and potency of deoxyarbutin (4-[(tetrahydro-2H-pyran-2-yl) oxy] phenol) tyrosinase inhibitors is well-known and well-documented in the literature. See, for example: Hamed, et al., J. Cosmet. Sci. 54(4) 2006 291-308; and Boissy, et al., Experimental Dermatology 14(8) 2005, 601-608. It is safer and less irritating than hydroquinone, However, all attempts to create a stable, non-browning topical formulation have been unsuccessful. It has been shown that deoxyarbutin is a thermolabile and acid sensitive compound in aqueous solutions and degraded to hydroquinone (Chao-Hsun Yang, et al., Int. J. Mol. Sci. 2010, 11, 3977-3987). It is known for its great sensitivity to hydrolysis, to oxidation and to heat, leading to generation of hydroquinone. U.S. Patent Application Pub. No. US2013/0224137, which describes a composition comprising deoxyarbutin. In this case, the hydroquinone is generated in significant amount over time. The commercial products, such as Prevage MD (Allergan) that contained deoxyarbutin, were withdrawn from the market, in part because the creams quickly became colored. An attempt to create a stable anhydrous topical formulation also failed (Chih-Chien Lin, et al., Int. J. Mol. Sci. 2011, 12, 5946-5954). The results of this study indicated that water increased the decomposition of deoxyarbutin in the formulations, and that a polyol-in-silicone, oil-based, anhydrous emulsion system provided a relatively stable surrounding for the deoxyarbutin that delayed its degradation at 25° C. and 45° C. However, generation of hydroquinone is still observed in relatively significant amount.
A formulation of a depigmenting agent, e.g., deoxyarbutin, in which the vehicle retarded oxidation and decomposition of depigmenting agent (e.g., retarded oxidation and decomposition of deoxyarbutin to hydroquinone) and was appropriate and acceptable for topical application, particularly to the face, would represent a significant improvement in the art.